1. Field of the Invention
This invention relates to the provision of heparin in an orally administrable form.
2. Description of the Prior Art
It has long been established that heparin is an effective and safe blood anticoagulant. However, therapeutic use of heparin is limited by the need to administer it parenterally. A great deal of effort has been spent on the development of adjuvants, derivatives, analogs and expedients to render heparin absorbable from the intestine, so that it may be orally administered. This effort includes adjuvants such as heparin co-administered with ethylenediaminetetraacetate, EDTA (Windsor et al, "Gastrointestinal Absorption of Heparin and Synthetic Heparinoids", Nature, 190, 263-264 (1961); Tidball et al, "Enhancement of Jejunal Absorption of Heparinoid by Sodium Ethylenediaminetetraacetate in the Dog", Proc. Soc. Exp. Biol. Med., 111, 713-715 (1962); Rebar et al, "Forderung der Gastrointestinalen Resorption von Heparin durch Calciumbindungsmittel", Experientia, 19, 141-142 (1963)), with dimethylsulfoxide, DMSO, and diethylsulfone, and their homologs (Koh, T. Y., "Intestinal Absorption of Heparin", Can. J. Biochem., 47, 951-954 (1969)); derivatives such as heparin that underwent partial desulfation and methylation (Salafsky et al, "Intestinal Absorption of a Modified Heparin", Proc. Soc. Exp. Biol. Med., 104, 62-65 (1960)) or heparinic acid and/or heparinic acid complexes (Koh et al, "Intestinal Absorption of Stable Heparin Acid Complexes," J. Lab. Clin. Med., 80(1), 47-55 (1972)); analogs (Jarrett et al, "Effect of Intravenous and Oral Admnistration of Heparinoids G 31150, G-31150-A, and of Nitrolotriacetic Acid on Blood Coagulation", Throm. Diath Haemorrh, 25, 187-200(1971)); and expedients, such as instillation of heparin in acidic solutions in the animal intestinal loop (Loomis, T. A., "Absorption of Heparin from the Intestine", Proc. Soc. Exp. Med., 101, 447-449 (1959); Sue, T. K., "Heparin, Physical and Biological Factors in Absorption" in "Heparin: Structure, Cellular Functions and Clinical Applications", Ed., N. M. McDuffie, Academic Press, New York, 1979, pp. 159-166). Windsor, U.S. Pat. No. 3,088,868, discloses orally administrable heparin comprising heparin complexed with the alkali metal salts of amino acids or polyaminepolyacids, e.g., salts of EDTA. Koh et al, U.S. Pat. Nos. 3,506,642 and 3,577,534, disclose heparin complexed with weakly basic compounds (pKB=7.0-12.5) being useful as an orally active medicament. However, too highly basic materials, e.g., aliphatic amines, are taught to produce materials which are not orally active. Engel et al, U.S. Pat. No. 3,574,832, discloses a heparin composition for oral, intraduodenal or rectal administration comprising heparin and a sulfate-tupe surfactant. Sache et al, U.S. Pat. No. 4,239,754, discloses orally active heparin compositions comprising heparin retained on or in liposomes, the lipids of said liposomes are preferably phospholipids comprising acyl chains derived from nonsaturated fatty acids.
While limited success has been achieved in the direction of increasing heparin absorbability from the intestine, these efforts have not yet reached the stage that heparin can be administered orally to give a sustaining systemic anticoagulant effect. In short, these efforts to develop an orally administered heparin for use in clinical anticoagulant therapy have so far been unsuccessful.
In related work, complexes of heparin with quaternary ammonium ions such as tridodecylmethyl ammonium chloride, TDMAC (Leininger et al, Science, 152, 1625(1966); Grode et al, J. Biomed. Mater. Res. Symp., 3,77 (1972)), benzalkonium chloride, BKC (Grode et al, J. Biomed. Mater. Res. Symp., 3,77 (1972); Gott, U. L., Adv. Exp. Med. Bio., 52 35 (1975)), and cetylpyridinium chloride, GPC (Schmer et al, Trans. Am. Soc. Artif. Intern. Organs, 22,654 (1976)), have been proven to render heparin soluble in organic solvents. The heparin-surfactant complexes have been successful in the coating of internal surfaces of plastic medical appliances. Chang, U.S. Pat. No. 3,522,346, discloses the preparation of non-thrombogenic microcapsules wherein the encapsulating membrane incorporates or has on its surface a quaternary ammonium-heparin complex. Suitable quaternary ammonium compounds are benzalkonium, cetyltrimethylammonium and cetyldimethylbenzyl-ammonium. Harumiya et al, U.S. Pat. No. 3,844,989, discloses antithrombogenic polymer compositions, useful in the production of medical appliances, comprising a polymer containing cationic monomer units and heparin internally bound thereto. Grotta, U.S. Pat. No. 3,846,353, discloses a method of making a non-thrombogenic plastic material by exposing the plastic to a water-insoluble, organic solvent-soluble long chain alkyl quaternary ammonium salt having 2-4 alkyl groups and then exposing the plastic to heparin. Subsequent exposure of the plastic to blood plasma failed to release heparin in an anticoagulant effective amount. Ericksson et al, U.S. Pat. No. 4,265,927, discloses a method of heparinizing the surface of a medical article by contacting the article with a complex of heparin and a cationic surfactant, preferably of the primary amine type. Marchisio et al, U.S. Pat. No. 3,865,723, discloses the use of polymers with a polyamidic-aminic structure to remove heparin from blood.
Surfactants like BKC and CPC are cationic surfactants and widely used as antimicrobials (The Extra Pharmacocopia, Matindale, 27th Ed., The Pharmaceutical Press, London (1977)) and are quite toxic, e.g., LD.sub.50 of CPC, i.v. (mouse) is 10 mg/kg, i.v. (rat) is 6 mg/kg (Registry of Toxic Effects of Chemical Substances, U.S. Dept. HEW, 1975 Edition). Their toxicity is related to those various biological effects of quaternary ammonium heads whose effects include the depolarization of muscle tissue and hemolysis of erythrocytes. Toxic symptoms include dyspnoea and cyanosis due to paralysis of the respiratory muscles, possibly leading to asphyxia (Gastmeier et al, Z. Ges. Gerich. Med., 65, 96 (1969)) and allergic reactions, after repetitive applications of quaternary ammonium salt solutions to the skin, which have been reported to occur in some patients (Morgan, J. K., Br. J. Clin. Prac. 22, 261 (1969); Lansdown et al, Br. J. Derm., 86, 361(1972)). It is also believed that the surfactant characteristics of the quaternary ammonium ion, particularly in the liver, causes additional alterations in a number of chemical, biological and transport phenomena (Bohr et al, "Labile Quaternary Ammonium Salt as Soft Antimicrobials", J. Med Chem. 23, 469-474 (1980)).
A need therefore continues to exist for an orally administrable heparin.